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Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182894 | GEO | 2022/06/05

REPOSITORIES: GEO

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High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance.

Project description:Following CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope loss can be caused by aberrant CD19 exon 2 processing, we herein investigate the regulatory code that controls CD19 splicing. We combine high-throughput mutagenesis with mathematical modelling to quantitatively disentangle the effects of all mutations in the region comprising CD19 exons 1-3. Thereupon, we identify ~200 single point mutations that alter CD19 splicing and thus could predispose B-ALL patients to developing CART-19 resistance. Furthermore, we report almost 100 previously unknown splice isoforms that emerge from cryptic splice sites and likely encode non-functional CD19 proteins. We further identify cis-regulatory elements and trans-acting RNA-binding proteins that control CD19 splicing (e.g., PTBP1 and SF3B4) and validate that loss of these factors leads to pervasive CD19 mis-splicing. Our dataset represents a comprehensive resource for identifying predictive biomarkers for CART-19 therapy.

| S-EPMC9500061 | biostudies-literature

Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: Minigene library RNA-seq

Project description:We developed a massively parallel reporter assay to determine the splicing effects of all mutations in the region comprising CD19 exons 1-3. Despite the great success of CART-19 (chimeric antigen receptor-armed autologous T-cells) immunotherapy to treat B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the targeted CD19 epitope. Since epitope loss can be caused by CD19 exon 2 mis-splicing, we set out to learn the regulatory code that controls CD19 alternative splicing.

2022-06-05 | GSE182892 | GEO

Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: Minigene library DNA-seq

2022-06-05 | GSE182891 | GEO

Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: PTBP1 iCLIP2 in NALM-6 cells

2022-06-05 | GSE182893 | GEO

Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance

Project description:Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance

| PRJNA758168 | ENA

Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: Minigene library DNA-seq

Project description:Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: Minigene library DNA-seq

| PRJNA758171 | ENA

Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: Minigene library RNA-seq

Project description:Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: Minigene library RNA-seq

| PRJNA758173 | ENA

Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy.

Project description:UnlabelledThe CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor-armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms.SignificanceCART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms.

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Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: PTBP1 iCLIP2 in NALM-6 cells

Project description:Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance: PTBP1 iCLIP2 in NALM-6 cells

| PRJNA758172 | ENA

Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19.

Project description: Not available

| S-EPMC7214268 | biostudies-literature